Method for the production of biperiden II

ABSTRACT

The invention relates to a method for the production of biperiden by reacting an exo/endo mixture of 1-(bicyclo[2.2.1.]hept-5-en-2-yl) 3-piperidino-1-propanone with a phenyl magnesium compound, wherein the exo/endo ratio of 1-(bicylo[2.2.1]hept-5-en-2-yl)-3-piperidino-1-propanone is at least 4.5:1.

This application is a 371 of PCT/EP02/05500 filed May 17, 2002.

The present invention relates to a method for the production ofbiperiden.

Biperiden is a well-known central anticholinergic agent and is employedfor the treatment of Parkinson's disease (Ullmanns Enzyklopädie dertechnischen Chemie, 4th edition, volume 21, Verlag Chemie, 1982, p.627). It comprises a racemate of1-(bicyclo[2.2.1]hept-5-en-2-yl(exo,R))-1-phenyl-3-piperidinopropanol(1,S) and1-(bicyclo[2.2.1]hept-5-en-2-yl(exo,S))-1-phenyl-3-piperidinopropanol(1,R)(Ia) and represents one of four possible pairs of enantiomers (Ia-d) ofthe amino alcohol1-(bicyclo[2.2.1]hept-5-en-2-yl)-1-phenyl-3-piperidino-1-propanol (I).

DE 1 005 067 and U.S. Pat. No. 2,789,110 describe the preparation of theamino alcohol I by reacting1-(bicyclo[2.2.1]hept-5-en-2-yl)-3-piperidino-1-propanone (II) with aphenylmagnesium halide. U.S. Pat. No. 2,789,110 additionally describesthe preparation of the propanone II starting from1-(bicyclo[2.2.1]hept-5-en-2-yl)-ethanone (III), paraformaldehyde andpiperidine hydrochloride in a Mannich reaction, and the preparation ofthe ethanone III from cyclopentadiene and methyl vinyl ketone in aDiels-Alder cycloaddition.

Neither DE 1 005 067 nor U.S. Pat. No. 2,789,110 disclose whether theamino alcohol I obtained in this way is a mixture of isomers or a pureisomer.

The precursor for preparing the propanol,1-(bicyclo[2.2.1]hept-5-en-2-yl)-3-piperidino-1-propanone (II), canexist in two isomeric forms, as exo or as endo isomer (II-exo, II-endo),and only the exo form is able to afford biperiden in the abovementionedreaction with a phenylmagnesium halide.

The structural formulae of II-exo and of II-endo show for the sake ofsimplicity in each case only one of two possible enantiomers of the exoisomer and endo isomer, respectively. However, the designation II-exo orII-endo relates hereinafter to the pair of enantiomers of the exo orendo form.

1-(Bicyclo[2.2.1]hept-5-en-2-yl)ethanone (III), the starting substancefor synthesizing the propanone II, may also exist both as exo and asendo isomer (III-exo, III-endo) and, correspondingly, only reaction ofthe exo isomer leads in the subsequent steps to biperiden.

The structural formulae of III-exo and of III-endo show for the sake ofsimplicity in each case only one of two possible enantiomers of the exoisomer and endo isomer, respectively. However, the designation III-exoor III-endo relates hereinafter to the pair of enantiomers of the exo orendo form.

It is not possible to infer any information about the configuration ofthe precursors III and intermediates II employed in any of theabovementioned publications.

It is known that 1-(bicyclo[2.2.1]hept-5-en-2-yl)ethanone (III) isobtained from the cycloaddition in an exo/endo ratio of 1:4 (e.g. R.Breslow, U. Maitra, Tetrahedron Letters, 1984, 25, 1239). Since theprior art mentioned at the outset makes no statements at all about thestereochemistry of the ethanone III, it must be assumed that theethanone III was employed in this ratio of isomers to prepare the aminoalcohol I.

The preparation of exo-1-(bicyclo[2.2.1]hept-5-en-2-yl)ethanone(III-exo) was described in 1965 by J. G. Dinwiddie and S. P. McManus (J.Org. Chem., 1965, 30, 766). This entails exo/endo mixtures of1-(bicyclo[2.2.1]hept-5-en-2-yl)ethanone (III) in which the endo contentpredominates being heated in methanol in the presence of sodiummethanolate and isomerizing to mixtures with an exo content of about70%. It is possible to obtain from this by fractional distillation and,where appropriate, redistillation of the distillateexo-1-(bicyclo[2.2.1]hept-5-en-2-yl)ethanone (III-exo) with a purity ofup to 95%.

Experiments by the applicant have shown that even on use of virtuallypure exo ethanone III-exo, i.e. of an ethanone III with an exo contentof at least 95%, as starting material of the Mannich reaction anexo/endo mixture of propanone II having a maximum exo/endo ratio of4.0:1 is always obtained. This is unsatisfactory as regards obtainingpure biperiden (Ia) from reaction of the propanone II with aphenylmagnesium compound. Pure biperiden means a biperiden (Ia) with apurity of at least 99.0%, as is generally necessary for pharmaceuticalapplications.

It is an object of the present invention to provide a method for theproduction of biperiden, which provides the latter in higher yield. Themeaning of biperiden is a substance of the structural formula Ia. It isparticularly intended to improve the selectivity of the propanone IIproduction in relation to the exo isomer.

We have found that this object is achieved by a method for theproduction of biperiden by reacting an exo/endo mixture of1-(bicyclo[2.2.1]hept-5-en-2-yl)-3-piperidin-1-propanone (II) with anexo/endo ratio of at least 4.5:1 with a phenylmagnesium compound,characterized in that the production of the exo/endo mixture of1-(bicyclo[2.2.1]hept-5-en-2-yl)-3-piperidino-1-propanone (II) comprisesthe following steps:

a) reaction of exo-1-(bicyclo[2.2.1]hept-5-en-2-yl)ethanone (III-exo)with a formaldehyde source and an acid addition salt of piperidine orwith a formaldehyde source and piperidine in the presence of an acid inan organic solvent or in a mixture thereof with water,

b) conversion of the resulting reaction mixture into an aqueous solutionand extraction of this aqueous solution with an organic solvent whichhas limited miscibility or is immiscible with water at a pH notexceeding 7, and

c) extraction of the raffinate obtained in b), which contains theexo/endo mixture of1-(bicyclo[2.2.1]hept-5-en-2-yl)-3-piperidino-1-propanone (II), at a pHof at least 7.5 with an organic solvent which has limited miscibility oris immiscible with water,

d) removal of the organic extract, purification of the organic extractby extraction with aqueous acid and subsequent removal of the solvent,resulting in 1-(bicyclo-[2.2.1]hept-5-en-2-yl)-3-piperidino-1-propanone(II) with an exo/endo ratio of at least 4.5:1.

The meaning of exo-1-(bicyclo[2.2.1]hept-5-en-2-yl)ethanone (III-exo)hereinafter is an ethanone III with an exo content of at least 96%.

The exo and endo isomers employed in the method of the inventioncomprise, as already described for the exo and endo ethanone III-exo andIII-endo and for the exo and endo propanone II-exo and II-endo, pairs ofenantiomers. In order to obtain biperiden (Ia), which is itself aracemate, racemic mixtures of enantiomers of the starting materials andof the intermediates are employed. However, the method of the inventioncan also be applied to pure enantiomers and to non-racemic mixtures ofenantiomers.

Reaction of exo-1-(bicyclo-[2.2.1]hept-5-en-2-yl)ethanone (III-exo) witha Mannich reaction with a formaldehyde source and an acid addition saltof piperidine or with a formaldehyde source and piperidine in thepresence of an acid generally takes place in a solvent suitable forMannich reactions. Suitable solvents are, in particular, C₁-C₄-alkanols,e.g. methanol, ethanol, n-propanol, isopropanol, sec-butanol orisobutanol, and mixtures thereof with water. Isopropanol is preferablyused.

Suitable acids are in principle the mineral acids or organic acidssuitable for Mannich aminomethylation.

Hydrochoric acid or hydrogen chloride or an organic sulfonic acid of thegeneral formula RSO₃H is preferably used. R in this case is a monovalentorganic radical, preferably C₁-C₄-alkyl, phenyl orC₁-C₄-alkyl-substituted phenyl, with methyl being particularlypreferred. The reaction can take place with the acid addition salt ofpiperidine or else with piperidine in the presence of an acid, in whichcase the acid addition salt of piperidine is formed in situ.

In this case, piperidine and the appropriate acid are preferablyemployed in equimolar amounts. In the case where the isolated acidaddition salt of piperidine is used, if the latter cannot be purchasedcommercially it can be prepared by reaction of piperidine with anappropriate acid in molar ratios in the range from 1:0.9 to 1:2,preferably in the range from 1:0.9 to 1:1.5, in particular in the rangefrom 1:0.9 to 1:1.2 and particularly preferably approximately equimolarand by a subsequent isolation.

The isolated acid addition salt of piperidine is preferably employed inthe Mannich reaction. Piperidine hydrochloride or piperidiniummethanesulfonate is particularly preferably employed.

The exo ethanone III-exo and the formaldehyde source are preferablyemployed in a molar ratio of from 1:1 to 1:2, the formaldehyde sourcebeing employed in particular in an excess of from 10 to 100 mol % andparticularly preferably from 10 to 30 mol %, e.g. 20 mol %. Gaseousformaldehyde, formalin, trioxane or paraformaldehyde are suitable asformaldehyde source. Paraformaldehyde is preferably used.

The exo ethanone III-exo and piperidine or the acid addition salt ofpiperidine are preferably employed in a molar ratio of from 1:0.9 to1:2, in particular from 1:0.95 to 1:1.5 and particularly preferably from1:1 to 1:1.3.

When hydrochloric acid or hydrogen chloride is used as acid, the exoethanone III-exo and piperidine or its acid addition salt are reacted ina molar ratio in the range from 1:0.9 to 1:1.5, preferably in the rangefrom 1:0.9 to 1:1.2 and particularly preferably approximately equimolar.In a special embodiment, the molar ratios of the components exo ethanoneIII-exo, piperidine or its acid addition salt and formaldehyde sourceare 1:1-1.01:1.2.

When a sulfonic acid is used, the exo ethanone III-exo and piperidine orits acid addition salt are usually employed in a molar ratio in therange from 1:1 to 1:2. Piperidine or its acid addition salt ispreferably employed in excess, preferably using an excess of from 10 to100 mol %, particularly preferably from 10 to 30 mol %, e.g. 20 mol %.Piperidine or its acid addition salt and the formaldehyde source are inthis case suitably employed in a molar ratio in the range from 1:0.9 to1:1.2, preferably approximately equimolar. In a special embodiment, themolar ratios of the components exo ethanone III-exo, piperidine or itsacid addition salt and formaldehyde source are 1:1.2:1.2.

The reaction temperature for the Mannich reaction is usually in therange from 0° C. to the boiling point of the reaction mixture. Heatingto reflux is preferred. The reaction usually takes from 2 to 24 hours,preferably 5 to 12 hours and particularly preferably from 5 to 8 hours.

The conversion of the reaction mixture obtained in step a) usually takesplace in such a way that firstly the organic solvent is removed from thereaction mixture, which is normally carried out by distillation,preferably under reduced pressure. The residue is then taken up wherenecessary in water, i.e. when a solid or oily residue is obtained. If anaqueous mixture is obtained, this can be diluted with water whereappropriate. The aqueous mixtures obtained in this way are extracted oneor more times to remove non-basic organic constituents—usually unreactedstarting material—with an organic solvent which has limited miscibilityor is immiscible with water, with the pH of the aqueous phase notexceeding a value of 7.0. Suitable solvents which have limitedmiscibility or are immiscible with water include C₅-C₈-aliphaticcompounds such as n-pentane or n-hexane, C₅-C₆-alicyclic compounds suchas cyclohexane, aromatic compounds such as benzene, toluene or xylenesand aliphatic C₄-C₈-ethers such as diethyl ether, tert-butyl methylether or diisopropyl ether, or mixtures thereof. Aliphatic C₄-C₈-ethers,in particular diisopropyl ether, are preferably used for the extraction.

The procedure for this is preferably such that firstly the aqueous[lacuna] which is usually still acidic is extracted with thewater-immiscible solvent. The aqueous mixture is preferably extractedmore than once, in particular 2 to 5 times and specifically 3 times.

The pH of the raffinate can then be raised with a base, maintaining at≦7, followed by extraction. This procedure is preferred. For thispurpose, the aqueous solution is preferably treated one or more timeswith a mixture of a base or of an aqueous basic solution and one or moreof the abovementioned solvents suitable for extracting the aqueousphase, preferably diisopropyl ether. The bases normally used are alkalimetal or alkaline earth metal hydroxides or alkali metal carbonates.Sodium hydroxide or potassium hydroxide or aqueous solutions thereof arepreferably used, in particular sodium hydroxide or sodium hydroxidedsolution. The total amount of base employed is in the range from 5 to 15mol %, preferably 8 to 10 mol %, relative to the amount of exo ethanoneIII-exo employed. The pH of the aqueous phase should not exceed pH 7during this.

The aqueous solution is then adjusted in step c) of the method of theinvention in one or more stages with one of the abovementioned bases oran aqueous basic solution, preferably sodium hydroxide or sodiumhydroxide solution, to a pH of at least 7.5, preferably in the rangefrom 7.5 to 9, in particular in the range from 8 to 8.5 and particuarlypreferably in the range from 8.1 to 8.3. In the stepwise basification ofthe aqueous phase, each addition of the base or of the aqueous basicsolution is followed by extraction of the aqueous solution suitably withone of the abovementioned organic solvents suitable for extracting theaqueous phase, preferably diisopropyl ether; with one-stage addition ofthe base or of the aqueous basic solution, this correspondingly takesplace subsequent thereto, in this case extracting where appropriate morethan once, e.g. three to five times, with the organic solvent.

The organic extracts, which contain the1-(bicyclo[2.2.1]hept-5-en-2-yl)-3-piperidino-1-propanone (II), areusually combined and purified in step d) by extraction with acid. Forthis purpose, the organic extract obtained in step c) is usually treatedwith an aqueous, in particular a dilute aqueous, acid. This can, whereappropriate, be followed by washing with water. Mineral acids such ashydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acidare generally used as acid, and hydrochloric acid is preferably used.The amount of acid employed is usually from 0.02 to 0.10 protonequivalent, preferably 0.03 to 0.05 proton equivalent, of the amount ofexo ethanone III-exo employed in the Mannich reaction. Protonequivalents mean the number of protons in an acid molecule. Theconcentration of the aqueous acid is usually in the range form 0.5 to 10M and in particular in the range from 2 to 7 M.

The organic extract is then freed of solvent, which preferably takesplace in vacuo.

The residue remaining after removal of the solvent by evaporation, whichconsists of at least 95% by weight of the exo/endo mixture of thepropanone II, contains the latter in an exo/endo ratio of at least4.5:1, in particular of at least 6:1, and in the case where piperidiniummethanesulfonate is used as starting material in the Mannich reaction ofat least 10:1, in particular of at least 15:1, e.g. of 22:1.

The exo/endo mixture of the propanone II obtained after the workup ofthe invention contains the exo propanone II-exo in a considerablygreater proportion than the exo/endo mixture of the propanone IIobtained after the usual workup by distillation, while the overall yieldof exo/endo propanone II is at least equally large.

The exo/endo mixture of1-(bicyclo[2.2.1]hept-5-en-2-yl)-3-piperidino-1-propanone (II) producedaccording to the invention is reacted in a Grignard reaction in asuitable solvent with a phenylmagnesium compound, preferably withdiphenylmagnesium or particularly preferably with a phenylmagnesiumcompound of the general formula

in which R′ is C₁-C₄-alkyl such as methyl, ethyl, n-propyl, isopropyl orn-butyl, C₄-C₆-cycloalkyl such as cyclohexyl,C₄-C₆-cycloalkyl-C₁-C₄-alkyl such as 2-cyclohexylethyl,phenyl-C₁-C₄-alkyl such as benzyl, 2-phenylethyl or 3-phenylpropyl,substituted phenyl-C₁-C₄-alkyl such as 3,4-(methylenedioxy)benzyl,heteroaryl such as 8-quinolyl, heteroaryl-C₁-C₄-alkyl such as furfuryl,2-thienylmethyl or 2-(2-thienyl)ethyl, or benzhydryl. Thephenylmagnesium compound of the formula depicted above is referred tobelow as phenylmagnesium alkoxide.

Suitable solvents are aromatic compounds such as benzene, toluene, orxylenes, acyclic or cyclic ethers having 4 to 6 C atoms, mixturesthereof or mixtures of them with aliphatic or alicyclic hydrocarbonssuch as n-hexane or cyclohexane. Examples of suitable alicyclic ethersare diethyl ether and tert-butyl methyl ether, and examples of suitablecyclic ethers are tetrahydrofuran and dioxane. Diethyl ether,tetrahydrofuran or dioxane or mixtures thereof are preferably used. Thesolvents are usually employed anhydrous, as normal for Grignardreactions.

The phenylmagnesium alkoxide is prepared in a generally known manner,e.g. by reacting diphenylmagnesium with an alcohol of the generalformula R′ OH in which R′ is as defined above. Diphenyl-magnesium andthe alcohol are for this purpose reacted in a molar ratio in the rangefrom 1:0.9 to 1:1.5, preferably in the range from 1:1 to 1:1.2 andparticularly preferably approximately equimolar. Diphenylmagnesium,which is usually generated in situ as described hereinafter, isordinarily introduced into one of the abovementioned solvents suitablefor Grignard reactions, and the alcohol is normally added in portionsover a period of from 5 minutes up to about one hour at a temperature offrom 0 to 80° C., preferably from 0 to 50° C. and particularlypreferably from 0 to 40° C. After the addition is complete, the mixturecan be left, or preferably stirred, in the same temperature range for 15minutes to 2 hours, preferably 15 minutes to one hour, until thereaction is complete.

The diphenylmagnesium employed in the method of the invention isproduced in a manner known per se. For example, dioxane can be added toa phenylmagnesium halide, e.g. phenylmagnesium chloride, in a suitablesolvent, thus shifting the Schlenk equilibrium to result indiphenylmagnesium and the corresponding magnesium halide-dioxanecomplex. The latter usually precipitates, but is preferably not removedfrom the solution. Suitable solvents are generally acyclic and cyclicethers preferably having 4 to 6 C atoms or mixtures thereof withaliphatic, alicyclic or aromatic hydrocarbons. Examples of suitableacyclic ethers are diethyl ether and tert-butyl methyl ether, and asuitable cyclic ether is tetrahydrofuran. The suitable aliphatic andalicyclic hydrocarbons include in particular n-hexane and cyclohexane,and examples of suitable aromatic hydrocarbons are benzene, toluene andxylenes.

Dioxane is ordinarily employed at least equimolar in relation to thephenylmagnesium halide. If diphenylmagnesium is to be used asphenylmagnesium compound, then dioxane is preferably employed in excess,for example in an excess of from 50 to 500 mol %, in particular from 100to 300 mol % and specifically of from 100 to 200 mol %. Ifdiphenylmagnesium is first to be converted into the phenylmagnesiumalkoxide, preferably dioxane and the phenylmagnesium halide are employedin a molar ratio in the range from 1:1 to 1.5:1, in particular 1:1 to1.2:1 and particularly preferably approximately equimolar.

The dioxane is added to the solution of the phenylmagnesium halideusually at a temperature in the range from −20 to 60° C., preferably inthe range from −10 to 40° C.

The mixture obtained after addition of the dioxane is normally left forfrom 15 minutes to 2 hours, preferably 20 minutes to one hour, in thetemperature range mentioned for the addition of the dioxane, before itis employed in the method of the invention.

Both the preparation of diphenylmagnesium, the reaction to give thephenylmagnesium alkoxide and the Grignard reaction of thephenylmagnesium compound with the propanone II are suitably carried outunder an inert gas atmosphere. Examples of suitable inert gases arenitrogen and the noble gases such as argon, and mixtures thereof.

In the Grignard reaction of the propanone II with the phenyl-magnesiumcompound, ordinarily the phenylmagnesium compound and the propanol IIare employed in a molar ratio in the range from 0.8:1 to 3:1, preferablyfrom 0.8:1 to 2:1 and in particular from 0.8:1 to 1.5:1. Wherediphenylmagnesium or the phenylmagnesium alkoxide is used, thephenylmagnesium compound and the propanone II are particularlypreferably employed in a molar ratio in the range from 1:1 to 1.3:1.

Ordinarily, the propanone II is added to the phenylmagnesium compound inthe form of a solution in one of the abovementioned organic solventssuitable for Grignard reactions at a temperature in the range from −20°C. to the boiling point of the reaction mixture, preferably in the rangefrom −10° to 90° C. and particularly preferably in the range from 0° C.to 70° C. The phenylmagnesium compound is moreover ordinarily employedin a concentration in the range from 0.1 to 10 mol/l, preferably in therange from 0.1 to 3 mol/l and particularly preferably in the range from0.2 to 2 mol/l.

The propanone II can be added in one portion or, preferably, over aperiod of from a few minutes up to several hours, e.g. 5 minutes to 5hours. The propanone II is added either in the form of a solution in oneof the abovementioned inert solvents suitable for Grignard reactions or,preferably, in pure form. When added as solution, the concentration ofthe propanone II is ordinarily from 0.1 to 20 mol/l, preferably 1 to 15mol/l. To complete the reaction, the reaction mixture is normally leftat a temperature in the range from −20° C. to the boiling point of thereaction mixture, preferably in the range from −10° C. to 90° C. andparticularly preferably in the range from 10° C. to 80° C. for from 15minutes to 5 hours, specifically 30 minutes to 2 hours, during which itis preferably stirred to improve mixing. Workup is, as usual forGrignard reactions, by aqueous extraction, e.g. by quenching thereaction mixture with water, an aqueous ammonium chloride solution or anacidic aqueous solution, with the pH of the resulting mixture in thelatter case subsequently being made alkaline, extracting the quenchedmixture, where appropriate after removal of an organic phase, with awater-immiscible solvent suitable for dissolving the product, andremoving the solvent from the extract or from the extract combined withthe organic phase. Examples of suitable solvents are aromatic compoundssuch as benzene or toluene, the abovementioned acyclic ethers, esterssuch as ethyl acetate or chlorine-containing aliphatic compounds such asdichloromethane or trichloromethane.

The crude product obtained from the reaction of the propanone II withdiphenylmagnesium or with the phenylmagnesium alkoxide consistsessentially of the four diastereomeric pairs of enantiomers Ia to Id of1-(bicyclo[2.2.1]hept-5-en-2-yl)-1-phenyl-3-piperidino-1-propanol (I),with the pair of enantiomers Ia (biperiden) forming the major quantity.The ratio of biperiden (Ia) to the other three pairs of enantiomers Ibto Id determined by gas chromatography is normally at least 1.5:1 and ispreferably in the range from 1.7:1 to 2.4:1. Particularly highproportions of the pair of enantiomers Ia are obtained for example whendiphenylmagnesium or phenylmagnesium benzyl alcoholate is reacted withthe propanone II which has been obtained from the reaction of the exoethanone III-exo with piperidinium methanesulfonate.

The biperiden (Ia) is isolated from the mixture of diastereomers bydissolving the latter with heating, preferably at a temperature of from40 to 80° C., in particular from 50 to 70° C., in a mixture of water anda polar, water-miscible organic solvent.

Suitable solvents are C₁-C₃-alkanols, i.e. methanol, ethanol, n-propanoland isopropanol. Aqueous isopropanol is preferably used, particularlypreferably 70 to 95% isopropanol and especially 90% isopropanol. Thepercentage data given here and hereinafter in relation to theisopropanol content are based on the volume of the isopropanol relativeto the total volume of the water-containing solvent. HCl is added tothis solution, for example in the form of a solution of hydrogenchloride in an organic solvent, preferably in one of the C₁-C₃-alkanolsmentioned, with preference in isopropanol, or in the form ofhydrochloric acid. HCl is employed at least equimolar in relation to theamino alcohol I, preferably in an excess of from 5 to 50 mol % andparticularly preferably from 5 to 20 mol %. The addition preferablytakes place at elevated temperature, e.g. at 40 to 80° C. and inparticular at 50 to 70° C. To complete the reaction after addition iscomplete, the reaction mixture is left at a temperature of from 50° C.up to the boiling point of the reaction mixture for 0.5 to 3 hours,preferably while stirring. In a preferred embodiment, the reactionmixture is stirred at 55 to 65° C. for the first two thirds of the timeand then stirred at the reflux temperature for one third of the time.The reaction mixture is then cooled to a temperature in the range from 0to 30° C., where appropriate stirred in this temperature range for up toseveral hours, e.g. up to 10 hours, preferably up to 5 hours, and thenthe hydrochloride which has formed is removed from the solution in aconventional way.

For further purification of the hydrochloride, it is generally taken upwet or dry in water and a sufficient amount of one or more polar dialkylethers of limited or zero miscibility with water and having 4 to 8 Catoms, such as diethyl ether, tert-butyl methyl ether and especiallydiisopropyl ether, and a suitable base is added to the mixture. Suitableamounts of organic solvents are, for example, from 4 to 10 ml of solventper gram of dry hydrochloride. Water and organic solvent are preferablyemployed in a ratio in the range from 1:2 to 1:5 by volume.

Suitable bases are alkali metal and alkaline earth metal hydroxides, andalkali metal carbonates; sodium or potassium hydroxide or their aqueoussolutions are particularly preferably used, sodium hydroxide or sodiumhydroxide solution are especially used. However, it is also possible touse water-soluble organic bases, for example amines having aliphaticsubstituents and 2 to 8 C atoms. The base is employed at leastequimolar, preferably in excess, in particular in an excess of from 5 to15 mol % based on the hydrochloride.

The reaction with the base preferably takes place at elevatedtemperature. For this purpose, before, during or, preferably, afteraddition of the base the mixture is heated to a temperature in the rangeof 25° C. up to the boiling point of the reaction mixture, preferably inthe range from 30 to 70° C., and when diisopropyl ether is used asdialkyl ether preferably in the range from 40 to 65° C., in particularfrom 55 to 60° C. This generally results in two clear phases which areseparated at elevated temperature, in the case where diisopropyl etheris used as dialkyl ether in the abovementioned temperature range. Theorganic phase is washed with water at elevated temperature, in the casewhere diisopropyl ether is used as dialkyl ether in the abovementionedtemperature range, and then concentrated preferably under atmosphericpressure by removing the solvent until the weight/volume ratio of theproduct to the solvent is in the range from 1:2 to 1:6, preferably from1:3 to 1:4.5. When the mixture is cooled to room temperature or below,but preferably not below −10° C., pure biperiden (Ia) crystallizes outand is isolated by conventional methods for isolating solids, e.g.filtering off the solid or decanting off the mother liquor.

It was possible by the use according to the invention of the propanoneII with a higher exo content to increase the yield of biperiden (Ia)considerably, especially in combination with the workup described above.

Biperiden (Ia) can then be converted with a pharmacologically acceptableacid in a conventional manner into its acid addition salt. Examples ofsuitable acids are hydrohalic acids, in particular hydrogen chloride orhydrochloric acid, and organic mono- or dicarboxylic acids such asacetic acid, oxalic acid, maleic acid, fumaric acid, lactic acid,tartaric acid, adipic acid or benzoic acid, also phosphoric acid andsulfuric acid, and the acids mentioned in Fortschritte derArzneimittelforschung, volume 10, pages 224 et seq., Birkhäuser Verlag,Basle, Stuttgart, 1966. Biperiden (Ia) is normally marketed ashydrochloride.

The exo-1-(bicyclo[2.2.1]hept-5-en-2-yl)ethanone (III-exo) used toprepare the 1-(bicyclo[2.2.1]hept-5-en-2-yl)-3-piperidino-1-propanone(II) is obtained by a Diels-Alder cycloaddition reaction ofcyclopentadiene and methyl vinyl ketone. A particularly advantageousmethod for preparing III, which affords a product with a high content ofIII-exo, is described in the parallel German patent application10124452.5, the disclosure of which is incorporated herein by reference.

The cycloaddition of cyclopentadiene and methyl vinyl ketone can inprinciple be carried out in a solvent conventional for such reactions,such as diethyl ether, benzene, toluene or xylene or else withoutsolvent. It is preferred to use no solvent. Cyclopentadiene and methylvinyl ketone are normally employed in a molar ratio in the range from3.0:1 to 0.5:1. They are preferably reacted equimolar or withcyclopentadiene in excess, with the excess preferably being 50 to 150mol %.

The reaction is usually carried out at temperature in the range from 0to 60° C., preferably in the range from 10 to 40° C.

Low-boiling constituents, usually unreacted precursors, are usuallyremoved following the cycloaddition by distillation under reducedpressure, preferably under 1 to 150 mbar. The remaining mixture, whichconsists of about 20% exo- and about 80%endo-1-(bicyclo[2.2.1]hept-5-en-2-yl)ethanone, is reacted with an alkalimetal C₁-C₄-alcoholate. The amount of alkali metal alcoholate is usuallyfrom 0.1 to 5% by weight, preferably from 0.2 to 2% by weight, based onthe total weight of the mixture. Sodium methanolate is preferably used.The temperature necessary for isomerization of the ethanone III isusually in the range from 50 to 110° C., preferably in the range from 60to 100° C. For this purpose, the mixture is often heated under reducedpressure to reflux, preferably under a pressure of from 1 to 100 mbarand in particular under a pressure of from 5 to 50 mbar. Theseconditions are usually applied for from 10 minutes to 5 hours, inparticular 20 minutes to 3 hours and specifically 0.5 hours to 2 hours,and then fractional distillation of the resulting mixture is started,preferably distilling out the exo isomer of III. It is assumed thatremoval of the exo isomer from the equilibrium promotes isomerization ofthe endo ethanone to the exo form. The fractional distillation normallytakes place through a column under reduced pressure, preferably in therange from 1 to 100 mbar, in particular from 1 to 50 and specificallyfrom 1 to 20 mbar. The distillation temperature (distillate temperature)is preferably adjusted to from 50 to 100° C. and specifically to 50 to80° C. In this way, exo-1-(bicyclo[2.2.1]-hept-5-en-2-yl)ethanone(III-exo) is obtained in a purity which is at least 96%. Redistillationof the distillate results in the exo ethanone III-exo with a purity ofup to 100%.

The following example serves to illustrate the invention but is not tobe understood as restrictive.

EXAMPLE

1. Preparation of the Starting Material

1.1 exo-1-(Bicyclo[2.2.1]hept-5-en-2-yl)ethanone (III-exo)

198.3 g of cyclopentadiene were rapidly added to 210.3 g of methyl vinylketone. After the addition was complete, the solution was stirred atroom temperature for one hour and then unreacted precursor was removedby distillation at a temperature of 58° C. and a pressure of 20 mbar.The residue from evaporation, mainly consisting of a mixture of the exoand the endo form of 1-(bicyclo[2.2.1]hept-5-en-2-yl)ethanone (III) inthe ratio of 1:4, was heated to reflux with 5 g of sodium methanolateunder a pressure of from 10 to 20 mbar for one hour. The reactionmixture was then distilled through a column at a temperature of 75° C.and a pressure of 20 mbar. This resulted in 298.3 g (73% of theory) ofexo-1-(bicyclo[2.2.1]hept-5-en-2-yl)ethanone (III-exo) in the form of apale yellowish oil.

1.2 1-(Bicyclo[2.2.1]hept-5-en-2-yl)-3-piperidino-1-propanone (II)

1.2.1 Preparation of1-(bicyclo[2.2.1]hept-5-en-2-yl)-3-piperidino-1-propanone (II) usingpiperidine hydrochloride

510.7 g of exo-1-(bicyclo[2.2.1]hept-5-en-2-yl)ethanone (III-exo), 460.6g of piperidine hydrochloride and 135.0 g of paraformaldehyde were keptat the reflux temperature in 950 ml of isopropanol for 7 hours. Thesolvent was removed in a rotary evaporator (pressure: 80 mbar; bath: 60°C.), and the residue was taken up in 1 000 ml of water. The solution waswashed three times with 300 ml of diisopropyl ether each time in orderto remove unreacted ethanone III. For purification, the washed aqueoussolution was mixed with 30 ml of 5M sodium hydroxide solution and 200 mlof diisopropyl ether and stirred for a quarter hour, and the organicphase was separated off. For further purification, the aqueous phase wasmixed with 20 ml of 5M sodium hydroxide solution and 200 ml ofdiisopropyl ether and again stirred for a quarter hour, and the organicphase was separated off. For purification again, the aqueous phase wasmixed anew with 20 ml of 5M sodium hydroxide solution and 200 ml ofdiisopropyl ether and stirred for a quarter hour, and the organic phasewas separated off. The remaining, purified aqueous phase was adjusted topH 7.8 with 105 ml of 50% strength sodium hydroxide solution andextracted with diisopropyl ether. This was done by adding 600 ml ofdiisopropyl ether, stirring for a quarter hour and separating off theorganic phase (1st alkaline extract). The aqueous phase was adjusted topH 8.2 with a further 60 ml of 5M sodium hydroxide solution and thenre-extracted with diisopropyl ether. This was done on this occasion byadding 300 ml of diisopropyl ether, stirring for a quarter hour andseparating off the organic phase (2nd alkaline extract). Alkalineextracts 1 and 2 were combined and mixed with 165 ml of water and 35 mlof 5M hydrochloric acid. The mixture was stirred for a quarter hour, theaqueous phase was separated off, and the organic phase was washed with200 ml of water and evaporated in a rotary evaporator (pressure: down to10 mbar; bath: 50° C.). The residue obtained from evaporation comprised473.5 g of an exo/endo mixture of the propanone II in the exo/endo ratio(GC) of 6.4:1 in the form of a pale brown oil; which is 54.1% of theory.

1.2.2 Preparation of1-(bicyclo[2.2.1]hept-5-en-2-yl)-3-piperidino-1-propanone (II) usingpiperidinium methanesulfonate

392.1 g of anhydrous methanesulfonic acid were added dropwise to 340.8 gof piperidine in 700 ml of isopropanol while stirring and cooling withwater over the course of one hour, during which the temperature rose to75° C. The dropping funnel was washed with 50 ml of isopropanol, and themixture was then cooled to 25° C. and stirred at this temperature forhalf an hour. The precipitated product was filtered off with suction,washed twice with 200 ml of diisopropyl ether each time and dried at 50°C. in vacuo. 688.9 g of piperidinium methanesulfonate were obtained ascolorless crystals; which is 95% of theory.

476.7 g of exo-1-(bicyclo[2.2.1]hept-5-en-2-yl)ethanone (III-exo), 761.5g of piperidinium methanesulfonate and 126.0 g of paraformaldehyde werekept at the reflux temperature in 950 ml of isopropanol for 7 hours. Thesolvent was removed in a rotary evaporator (pressure: 80 mbar; bath: 60°C.), and the residue was taken up in 1 000 ml of water. The solution waswashed three times with 300 ml of diisopropyl ether each time in orderto remove unreacted ethanone III. For purification, the washed solutionwas mixed with 30 ml of 5M sodium hydroxide solution and 200 ml ofdiisopropyl ether and stirred for a quarter hour, and the organic phasewas separated off. For further purification, the aqueous phase was mixedwith 20 ml of 5M sodium hydroxide solution and 200 ml of diisopropylether and again stirred for a quarter hour, and the organic phase wasseparated off. For purification again, the aqueous phase was mixed anewwith 20 ml of 5M sodium hydroxide solution and 200 ml of diisopropylether and stirred for a quarter hour, and the organic phase wasseparated off. The remaining, purified aqueous phase was adjusted to pH7.8 with 90 ml of 50% strength sodium hydroxide solution and extractedwith diisopropyl ether. This was done by adding 600 ml of diisopropylether, stirring for a quarter hour and separating off the organic phase(1st alkaline extract). The aqueous phase was adjusted to pH 8.2 with afurther 70 ml of 5M sodium hydroxide solution and then re-extracted withdiisopropyl ether. This was done on this occasion by adding 300 ml ofdiisopropyl ether, stirring for a quarter hour and separating off theorganic phase (2nd alkaline extract). Alkaline extracts 1 and 2 werecombined and mixed with 165 ml of water and 35 ml of 5M hydrochloricacid. The mixture was stirred for a quarter hour, the aqueous phase wasseparated off, and the organic phase was washed with 200 ml of water andthe solvent was removed in a rotary evaporator (pressure: down to 10mbar; bath: 50° C.). The residue obtained from evaporation comprised440.9 g of an exo/endo mixture of the propanone II in the exo/endo ratio(GC) of 22:1 in the form of a pale brown oil; which is 54.0% of theory.

2. Production of biperiden (Ia)

2.1 Production of biperiden using diphenylmagnesium

2.1.1 Production of biperiden using diphenylmagnesium and1-(bicyclo[2.2.1]hept-5-en-2-yl)-3-piperidino-1-propanone (II) from thereaction described in 1.2.1

800 ml of dioxane were added to 2 000 g of a 25% strength solution ofphenylmagnesium chloride in tetrahydrofuran while stirring and coolingslightly over the course of one hour. The temperature rose to 28° C.during this, and a precipitate formed (magnesium chloride-dioxanecomplex). After addition of dioxane was complete, 387.4 g of an exo/endomixture of the propanone II obtained as in example 1.2.1 were added overthe course of one hour without cooling. The temperature rose to 58° C.during this. The dropping funnel was washed with 30 ml of dioxane, andthe mixture was then heated to the reflux temperature and kept at thistemperature for one hour. After cooling to 20° C., the mixture was addedto 800 g of ice and 600 ml of water while stirring. The mixture wasstirred for a quarter hour, during which the temperature rose to 40° C.The organic phase was separated off, and the aqueous phase was extractedtwice with 500 ml of diisopropyl ether each time. The organic phaseswere combined and washed twice with 500 ml of water each time, and thesolvent was removed in a rotary evaporator (pressure: down to 10 mbar;bath: 70° C.). The residue from evaporation—532 g of a mixture whichconsisted essentially of the pair of enantiomers Ia to Id of1-(bicyclo-[2.2.1]hept-5-en-2-yl)-1-phenyl-3-piperidino-1-propanol (I)in the ratio (GC) 22.3:7.2:2.8:1 (residual content of propanone II inthe residue from evaporation: 5.7%)—was dissolved in 4 450 ml of 90%strength isopropanol at 60° C. and, at this temperature, 330 ml of 5Mhydrochloric acid were added to the solution. Addition of the acid wasfollowed by stirring at 60° C. for one hour and then at the refluxtemperature for half an hour. After cooling to room temperature, thecrystals which had separated out were removed and washed twice with 250ml of isopropanol each time. The moist hydrochloride obtained in thisway (320 g; corresponding to 204 g dry) was introduced into 1 175 ml ofdiisopropyl ether and 350 ml of water and, while stirring, 130 ml of 5Msodium hydroxide solution were added. The mixture was heated to 55° C.and then the aqueous phase was separated off at this temperature, andthe diisopropyl ether solution was washed twice with 200 ml of watereach time. 530 ml of solvent were removed from the washed diisopropylether solution by distillation under atmospheric pressure. The residuefrom distillation was cooled. After stirring in an ice bath for onehour, the crystals which had separated out were removed, washed with 50ml of diisopropyl ether and dried at 50° C. in vacuo. 139.0 g ofbiperiden (Ia) were obtained as colorless crystals of melting point 112to 114° C. (Ullmanns Enzyklopädie der techn. Chemie, 4th edition, volume21, Verlag Chemie, 1982, page 627: 112-114° C.); which is 26.9% oftheory.

2.1.2 Production of biperiden using diphenylmagnesium and1-(bicyclo[2.2.1]hept-5-en-2-yl)-3-piperidino-1-propanone (II) from thereaction described in 1.2.2

400 ml of dioxane were added to 1 000 g of a 25% strength solution ofphenylmagnesium chloride in tetrahydrofuran while stirring and coolingslightly over the course of one hour. The temperature rose to 27° C.during this, and a precipitate formed (magnesium chloride-dioxanecomplex). After addition of dioxane was complete, 193.8 g of an exo/endomixture of the propanone II obtained as in example 1.2.2 were added overthe course of one hour without cooling. The temperature rose to 50° C.during this. The dropping funnel was washed with 30 ml of dioxane, andthe mixture was then heated to the reflux temperature and kept at thistemperature for one hour. After cooling to 15° C., the mixture was addedto 400 g of ice and 300 ml of water while stirring. The mixture wasstirred for a quarter hour, during which the temperature rose to 38° C.The organic phase was separated off, and the aqueous phase was extractedtwice with 250 ml of diisopropyl ether each time. The organic phaseswere combined and washed twice with 250 ml of water each time, and thesolvent was removed in a rotary evaporator (pressure: down to 10 mbar;bath: 70° C.). The residue from evaporation—254 g of a mixture whichconsisted essentially of the pair of enantiomers Ia to Id of1-(bicyclo-[2.2.1]hept-5-en-2-yl)-1-phenyl-3-piperidino-1-propanol (I)in the ratio (GC) 41.4:14.2:2.3 (residual content of propanone II in theresidue from evaporation: 7.2%)—was dissolved in 2 225 ml of 90%strength isopropanol at 60° C. and, at this temperature, 170 ml of 5Mhydrochloric acid were added to the solution. Addition of the acid wasfollowed by stirring at 60° C. for one hour and then at the refluxtemperature for half an hour. After cooling to room temperature, thecrystals which had separated out were removed and washed twice with 100ml of isopropanol each time. The moist hydrochloride obtained in thisway (175 g; corresponding to 102.4 g dry) was introduced into 600 ml ofdiisopropyl ether and 200 ml of water and, while stirring, 70 ml of 5Msodium hydroxide solution were added. The mixture was heated to 55° C.and then the aqueous phase was separated off at this temperature, andthe diisopropyl ether solution was washed twice with 100 ml of watereach time. 300 ml of solvent were removed from the washed diisopropylether solution by distillation under atmospheric pressure. The residuefrom distillation was cooled. After stirring in an ice bath for onehour, the crystals which had separated out were removed, washed with 30ml of diisopropyl ether and dried at 50° C. in vacuo. 70.6 g ofbiperiden (Ia) were obtained as colorless crystals of melting point 112to 114° C. (Ullmanns Enzyklopädie der techn. Chemie, 4th edition, volume21, Verlag Chemie, 1982, page 627: 112-114° C.); which is 27.4% oftheory.

2.2 Production of biperiden using phenylmagnesium benzyl alcoholate

2.2.1 Production of biperiden using phenylmagnesium benzyl alcoholateand 1-(bicyclo[2.2.1]hept-5-en-2-yl)-3-piperidino-1-propanone (II) fromthe reaction described in 1.2.1

322 g of dioxane were added to 2 000 g of a 25% strength solution ofphenylmagnesium chloride in tetrahydrofuran while stirring and coolingslightly over the course of half an hour. The temperature rose to 27° C.during this, and a precipitate formed (magnesium chloride-dioxanecomplex). After the addition of dioxane was complete, 197.5 g of benzylalcohol were added dropwise while cooling at a temperature not exceeding30° C. over the course of half an hour. Then, without cooling, 387.4 gof an exo/endo mixture of the propanone II obtained as in example 1.2.1were added over the course of one hour. The temperature rose to 55° C.during this. The mixture was subsequently heated to the refluxtemperature and kept at this temperature for one hour. After cooling to20° C., the mixture was added to 800 g of ice and 600 ml of water withstirring. After stirring for a quarter hour, the organic phase wasseparated off and the aqueous phase was extracted twice with 500 ml ofdiisopropyl ether each time. The organic phases were combined and washedtwice with 500 ml of water each time, and the solvent was removed in arotary evaporator (pressure: down to 10 mbar; bath: 70° C.). The residuefrom evaporation—690 g of a mixture which consisted essentially of thepairs of enantiomers Ia to Id of1-(bicyclo[2.2.1]hept-5-en-2-yl)-1-phenyl-3-piperidino-1-propanol (I) inthe ratio (GC) 18.3:6.0:3.2:1 (residual content of propanone II in theresidue for evaporation: 1.1%)—whilst dissolved in 4 450 ml of 90%strength isopropanol at 60° C. and, at this temperature, 310 ml of 5Mhydrochloric acid were added to the solution. The addition of acid wasfollowed by stirring at 60° C. for one hour and then at the refluxtemperature for half an hour. After cooling to room temperature, thecrystals which had separated out were removed and washed twice with 250ml of isopropanol each time. The moist hydrochloride obtained in thisway (398 g; corresponding to 238.8 g dry) was introduced into 1 350 mlof diisopropyl ether and 400 ml of water, and 150 ml of 5M sodiumhydroxide solution were added. The mixture was heated to 55° C. and, atthis temperature, the aqueous phase was separated off and thediisopropyl ether solution was washed twice with 200 ml of water eachtime. 600 ml of solvent was removed from the washed diisopropyl ethersolution by distillation under atmospheric pressure. The residue fromdistillation was cooled. After stirring in an ice bath for one hour, thecrystals which had separated out were removed, washed with 50 ml ofdiisopropyl ether and dried at 50° C. in vauo. 161.4 g of biperiden (Ia)were obtained as colorless crystals of melting point 112 to 114° C.(Ullmanns Enzyklopädie der techn. Chemie, 4th edition, volume 21, VerlagChemie, 1982, page 627: 112-114° C.); which is 31.2% of theory.

2.2.2 Production of biperiden using phenylmagnesium benzyl alcoholateand 1-(bicyclo[2.2.1]hept-5-en-2-yl)-3-piperidino-1-propanone (II) fromthe reaction described in 1.2.2

322 g of dioxane were added to 2 000 g of a 25% strength solution ofphenylmagnesium chloride in tetrahydrofuran while stirring and coolingslightly over the course of half an hour. The temperature rose to 27° C.during this, and a precipitate formed (magnesium chloride-dioxanecomplex). After the addition of dioxane was complete, 197.5 g of benzylalcohol were added dropwise while cooling at a temperature not exceeding30° C. over the course of half an hour. Then, without cooling, 387.4 gof an exo/endo mixture of the propanone II obtained as in example 1.2.2were added over the course of one hour. The temperature rose to 55° C.during this. The mixture was subsequently heated to the refluxtemperature and kept at this temperature for one hour. After cooling to20° C., the mixture was added to 800 g of ice and 600 ml of water withstirring. After stirring for a quarter hour, the organic phase wasseparated off and the aqueous phase was extracted twice with 500 ml ofdiisopropyl ether each time. The organic phases were combined and washedtwice with 500 ml of water each time, and the solvent was removed in arotary evaporator (pressure: down to 10 mbar; bath: 70° C.). The residuefrom evaporation—682.8 g of a mixture which consisted essentially of thepairs of enantiomers Ia to Id of1-(bicyclo-[2.2.1]hept-5-en-2-yl)-1-phenyl-3-piperidino-1-propanol (I)in the ratio (GC) 47.0:15.1:3.6:1 (residual content of propanone II inthe residue for evaporation: 0.8%—whilst dissolved in 4 450 ml of 90%strength isopropanol at 60° C. and, at this temperature, 310 ml of 5Mhydrochloric acid were added to the solution. The addition of acid wasfollowed by stirring at 60° C. for one hour and then at the refluxtemperature for half an hour. After cooling to room temperature, thecrystals which had separated out were removed and washed twice with 250ml of isopropanol each time. The moist hydrochloride obtained in thisway (400 g; corresponding to 216.6 g dry) was introduced into 1 350 mlof diisopropyl ether and 400 ml of water, and 150 ml of 5M sodiumhydroxide solution were added. The mixture was heated to 55° C. and, atthis temperature, the aqueous phase was separated off and thediisopropyl ether solution was washed twice with 200 ml of water eachtime. 600 ml of solvent was removed from the washed diisopropyl ethersolution by distillation under atmospheric pressure. The residue fromdistillation was cooled. After stirring in an ice bath for one hour, thecrystals which had separated out were removed, washed with 50 ml ofdiisopropyl ether and dried at 50° C. in vacuo. 161.4 g of biperiden(Ia) were obtained as colorless crystals of melting point 112 to 114° C.(Ullmanns Enzyklopädie der techn. Chemie, 4th edition, volume 21, VerlagChemie, 1982, page 627: 112-114° C.); which is 29.1% of theory.

3. Production of biperiden hydrochloride

93.4 g biperiden (Ia) were dissolved in 1 000 ml of isopropanol byheating to the reflux temperature. The solution was filtered hot and thefilter was washed with 100 ml of isopropanol. 65 ml of 5M hydrochloricacid were added to the combined filtrates at 75° C. The mixture was thenheated to reflux for 15 minutes. After cooling to room temperature itwas stirred for one hour, and the precipitated solid was filtered offwith suction, washed twice with 50 ml of isopropanol each time and driedat 70° C. in vacuo. 103.2 g of biperiden hydrochloride were obtained inthe form of colorless crystals of melting point 278 to 280° C. (UllmannsEnzyklopädie der techn. Chemie, 4th edition, volume 21, Verlag Chemie,1982, page 627: 278-280° C.); which is 98.9% of theory.

We claim:
 1. A method for the production of biperiden by reacting anexo/endo mixture of1-(bicyclo[2.2.1]hept-5-en-2-yl)-3-piperidino-1-propanone with anexo/endo ratio of at least 4.5:1 with a phenylmagnesium compound,characterized in that the production of the exo/endo mixture of1-(bicyclo-(2.2.1]hept-5-en-2-yl)-3-piperidino-1-propanone comprises thefollowing steps: a) reaction ofexo-1-(bicyclo[2.2.1]hept-5-en-2-yl)ethanone with a formaldehyde sourceand an acid addition salt of piperidine or with a formaldehyde sourceand piperidine in the presence of an acid in an organic solvent or in amixture thereof with water, b) conversion of the resulting reactionmixture into an aqueous solution and extraction of this aqueous solutionwith an organic solvent which has limited miscibility or is immisciblewith water at a pH not exceeding 7, c) extraction of the aqueousraffinate obtained in b), which contains the exo/endo mixture of1-(bicyclo[2.2.1]hept-5-en-2-yl)-3-piperidino-1-propanone, at a pH of atleast 7.5 with an organic solvent which has limited miscibility or isimmiscible with water, and d) removal of the organic extract,purification of the organic extract by extraction with acid andsubsequent removal of the solvent, resulting in1-(bicyclo-[2.2.1]hept-5-en-2-yl)-3-piperidino-1-propanone with anexo/endo ratio of at least 4.5:1.
 2. The method of claim 1,characterized in that an organic sulfonic acid of the general formulaRS0₃H in which R is C₁-C₄-alkyl, phenyl or C₁-C₄-alkyl-substitutedphenyl is used as the acid in step a).
 3. The method of claim 2,characterized in that methanesulfonic acid is employed.
 4. The method ofclaim 3, characterized in that piperidinium methanesulfonate is employedas the acid addition salt of piperidine in step a).
 5. The method ofclaim 1, characterized in that piperidine hydrochloride or piperidine inthe presence of hydrochloric acid or hydrogen chloride is employed instep a).
 6. The method of claim 1, characterized in that the molar ratioof exo-1-(bicyclo-(2.2.1]hept-5-en-2-yl)ethanone and piperidine or itsacid addition salt in step a) is in the range from 1:0.9 to 1:2.
 7. Themethod of claim 1, characterized in that the formaldehyde source isemployed in step a) in an excess of from 10 to 100 mol % relative to theexo-1-(bicyclo[2.2.1]hept-5-en-2-yl)ethanone.
 8. The method of claim 1,characterized in that after removal of the organic solvent in step b)the reaction mixture from step a) is converted into an aqueous solution,firstly extracted with an organic solvent of limited or zero miscibilitywith water, the pH of the aqueous raffinate is adjusted to a value notexceeding 7 by adding a base or a basic aqueous solution, where thetotal amount of base used is from 5 to 15 mol % of the amount ofexo-1-(bicyclo[2.2.1]hept-5-en-2-yl)ethanone used in step a), and againextracted with an organic solvent of limited or zero miscibility withwater.
 9. The method of claim 1, characterized in that the pH isadjusted in step c) to a value in the range from 8.0 to 8.5.
 10. Themethod of claim 1, characterized in that a mineral acid is used in stepd) for extraction with acid.
 11. The method of claim 10, characterizedin that the acid is employed in an amount of from 0.02 to 0.1 protonequivalents based on the amount ofexo-1-(bicyclo[2.2.1]-hept-5-en-2-yl)ethanone employed in step a). 12.The method of claim 1, characterized in that paraformaldehyde is used asthe formaldehyde source in step a).
 13. The method of claim 1,characterized in that diphenylmagnesium or a phenylmagnesium compound ofthe general formula

where R′ is C₁-C₄-alkyl, C₄-C₆-cycloalkyl, C₄-C₆-cycloalkyl-C₁-C₄-alkyl,phenyl-C₁-C₄-alkyl, substituted phenyl-C₁-C₄-alkyl, heteroaryl,heteroaryl-C₁-C₄-alkyl or benzhydryl, is used as the phenylmagnesiumcompound.
 14. The method as of claim 1, characterized in that theisolation of biperiden from the mixture of isomers of the1-(bicyclo[2.2.1]hept-5-en-2-yl)-1-phenyl-3-piperidino-1-propanol formedin the reaction of the exo/endo, mixture of1-(bicyclo[2.2.1]hept-5-en-2-yl)-3-piperidino-1-propanone with thephenylmagnesium compound comprises the following steps: reaction of themixture of isomers with HC1 in a mixture of water and a polar organicsolvent of limited or infinite miscibility with water, and isolation ofthe hydrochloride formed thereby, reaction of the hydrochloride in amixture of water and at least one polar dialkyl ether having limited orzero miscibility with water and having 4 to 8 C atoms with a base,separation of the two phases which have formed at elevated temperature,evaporation of part of the ether from the organic phase andcrystallization of the biperiden by cooling. 15.1-(Bicyclo[2.2.1]hept-5-en-2-yl)-1-phenyl-3-piperidino-1-propanonehaving an exo/endo ratio of at least 4.5:1.